Journal
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
Volume 16, Issue 14, Pages 6398-6406Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c3cp53962h
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Funding
- Extreme Science and Engineering Discovery Environment (XSEDE) [TG-MCA93S013]
- NSF [MCB1020765]
- NIH [GM31749]
- Howard Hughes Medical Institute
- Center for Theoretical Biological Physics (CTBP)
- National Biomedical Computation Resource (NBCR)
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM031749] Funding Source: NIH RePORTER
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G-protein coupled receptors (GPCRs) mediate cellular responses to various hormones and neuro-transmitters and are important targets for treating a wide spectrum of diseases. They are known to adopt multiple conformational states (e. g., inactive, intermediate and active) during their modulation of various cell signaling pathways. Here, the free energy landscape of GPCRs is explored using accelerated molecular dynamics (aMD) simulations as demonstrated on the M2 muscarinic receptor, a key GPCR that regulates the human heart rate and contractile forces of cardiomyocytes. Free energy profiles of important structural motifs that undergo conformational transitions upon GPCR activation and allosteric signaling are analyzed in detail, including the Arg(3.50)-Glu(6.30) ionic lock, the Trp(6.48) toggle switch and the hydrogen bonding interactions between Tyr(5.58)-Tyr(7.53).
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